The insulin-like growth factor-1 receptor (IGF-1R) plays an important role in proliferation, protection against apoptosis and transformation of malignant cells. The IGF-1R is also important for maintaining the malignant phenotype of tumour cells, and is involved in tumour cell protection against anti-tumour therapy. In contrast, the IGF-1R does not seem to be an absolute requirement for normal cell growth.
The IGF-1R consists of two identical extracellular α-subunits that are responsible for ligand binding, and two identical β-subunits with transmembrane domain and an intracellular tyrosine kinase domain. The ligand-receptor interaction results in phosphorylation of tyrosine residues in the tyrosine kinase domain, which spans from amino acid 973 to 1229, of the β-subunit. The major sites for phosphorylation are the clustered tyrosines at position 1131, 1135 and 1136 (LeRoith, D., et al., Endocr Rev 1995 April; 16(2), 143-63). After autophosphorylation the receptor kinase phosphorylates intracellular proteins, like insulin receptor substrate-1 and Shc, which activate the phosphatidyl inositol-3 kinase and the mitogen-activated protein kinase signalling pathways, respectively.
Based on the pivotal role of IGF-1R in malignant cells, it becomes more and more evident that IGF-1R is a target for cancer therapy (Baserga, R., et al., Endocrine Vol. 7, no. 1, 99-102, August 1997). One strategy to interfere with IGF-1R activity is to induce selective inhibition of the IGF-1R tyrosine kinase. However, there are today no available selective inhibitors of IGF-1R.
Drugs containing the notoriously toxic cyclolignan podophyllotoxin have been used for centuries, and its anti-cancer properties have attracted particular interest. Undesired side effects of podophyllotoxin have, however, prevented its use as an anti-cancer drug. The mechanism for the cytotoxicity of podophyllotoxin has been attributed to its binding to β-tubulin, leading to inhibition of microtubule assembly and mitotic arrest. The trans conformation in the lactone ring of podophyllotoxin has been shown to be required for binding to β-tubulin. In contrast, its stereoisomer picropodophyllotoxin, which has a cis configuration in the lactone ring, has a 50-fold lower inhibitory effect on microtubule polymerisation and a more than 35-fold higher LD50 in rats. Because of the low anti-microtubule effect of picropodophyllotoxin this compound has attracted little interest. During the last decades the major interest on podophyllotoxin derivatives has concerned etoposide, which is an ethylidene glucoside derivative of 4′-demethyl-epi-podophyllotoxin. Etoposide, which has no effect on microtubules, is a topoisomerase II inhibitor, and is currently being used as such in cancer therapy.